CRBM, University of Montpellier, CNRS, 1919 route de Mende, 34293 Montpellier, France.
Department of Genetics, Institut Curie, Paris 75005, France.
J Cell Sci. 2022 Apr 1;135(7). doi: 10.1242/jcs.259178. Epub 2022 Apr 8.
Altered endocytosis and vesicular trafficking are major players during tumorigenesis. Flotillin overexpression, a feature observed in many invasive tumors and identified as a marker of poor prognosis, induces a deregulated endocytic and trafficking pathway called upregulated flotillin-induced trafficking (UFIT). Here, we found that in non-tumoral mammary epithelial cells, induction of the UFIT pathway promotes epithelial-to-mesenchymal transition (EMT) and accelerates the endocytosis of several transmembrane receptors, including AXL, in flotillin-positive late endosomes. AXL overexpression, frequently observed in cancer cells, is linked to EMT and metastasis formation. In flotillin-overexpressing non-tumoral mammary epithelial cells and in invasive breast carcinoma cells, we found that the UFIT pathway-mediated AXL endocytosis allows its stabilization and depends on sphingosine kinase 2, a lipid kinase recruited in flotillin-rich plasma membrane domains and endosomes. Thus, the deregulation of vesicular trafficking following flotillin upregulation, and through sphingosine kinase 2, emerges as a new mechanism of AXL overexpression and EMT-inducing signaling pathway activation.
改变的内吞作用和囊泡运输是肿瘤发生过程中的主要参与者。在许多侵袭性肿瘤中观察到的 flotillin 过表达被认为是预后不良的标志物，它诱导了一种失调的内吞和运输途径，称为上调的 flotillin 诱导的运输（UFIT）。在这里，我们发现在非肿瘤性乳腺上皮细胞中，UFIT 途径的诱导促进上皮间质转化（EMT），并加速包括 AXL 在内的几种跨膜受体在内的 flotillin 阳性晚期内体中的内吞作用。AXL 的过表达在癌细胞中经常观察到，与 EMT 和转移形成有关。在 flotillin 过表达的非肿瘤性乳腺上皮细胞和侵袭性乳腺癌细胞中，我们发现 UFIT 途径介导的 AXL 内吞作用允许其稳定，并依赖于鞘氨醇激酶 2，这是一种在富含 flotillin 的质膜域和内体中募集的脂质激酶。因此，flotillin 上调后囊泡运输的失调，以及通过鞘氨醇激酶 2，成为 AXL 过表达和 EMT 诱导信号通路激活的新机制。
